梅尔特克
背向效应
医学
癌症研究
肿瘤微环境
放射治疗
免疫检查点
免疫系统
免疫疗法
CD8型
免疫学
内科学
受体酪氨酸激酶
受体
作者
Mauricio S. Caetano,Ahmed I. Younes,Hampartsoum B. Barsoumian,Michael Quigley,Hari Menon,Chan Gao,Thomas E. Spires,Timothy P. Reilly,Alexandra P. Cadena,Taylor R. Cushman,Jonathan E. Schoenhals,Ailin Li,Quynh-Nhu Nguyen,María Angélica Cortez,James W. Welsh
标识
DOI:10.1158/1078-0432.ccr-19-0795
摘要
Abstract Purpose: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy. Experimental Design: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response. Results: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8+ and NK cells populations measured by granzyme B expression with upregulation of CD8+CD103+ tissue-resident memory cells (TRM) within the abscopal tumor microenvironment relative to radiation only. Conclusions: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of TRM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.
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